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Indian Journal of Community Medicine

Safety of Equine Rabies Immunoglobulin in Grade III bites

Author(s): VS Chawan, RK Tripathi, L Sankhe, AC Fernandes, GV Daftary

Vol. 32, No. 1 (2007-01 - 2007-03)

VS Chawan(1), RK Tripathi(1), L Sankhe(2), AC Fernandes(3), GV Daftary(3)

A projected estimate of the annual human rabies incidence in India was 20,5651 and 55,000 deaths occur all over the world2. Almost all human deaths caused by rabies worldwide originate from Asia and Africa with 56% of the deaths estimated to occur in Asia and 44% in Africa. Passive immunization is highly recommended to provide immediate protection from development of rabies, along with the first dose of the vaccine. Passive immunization can be offered by injecting Rabies Immunoglobulin (RIG), human or equine, at the site of the wound. RIG neutralizes the virus at the site of the bite and prevents its progression into the CNS. It offers protection, which starts immediately after administration and lasts approximately 7 to 10 days, during which period active immunity to rabies can develop and thus, protect the individual. RIG can be administered irrespective of the interval between the time of exposure and initiation of vaccine treatment.

Equine rabies immunoglobulin (ERIG) is economical as compared to human rabies immunoglobulin (HRIG)3 and hence more affordable to patients in developing countries, like India. However, ERIG has potential to cause anaphylaxis, serum sickness and other allergic reactions and thus, physicians are hesitant to use it. This Phase IV study was planned to confirm its safety and efficacy for human use, among patients with Grade III severity animal bites.

Material and Methods

A prospective, open, non-comparative, multicentric, post-marketing surveillance study was designed and the necessary permission for conducting the trial taken from the respective Ethics committees at the centers in Mumbai, Delhi and Pune in India.

The manufacturing process of the study drug (Equirab, Bharat Serums and Vaccines Ltd, Mumbai), involves two vital steps, namely, enzyme refinement and caprylic acid precipitation, which ensure low risk of anaphylactic reactions. The enzyme treatment cleaves the IgG molecule into Fc and Fab fragments so as to obtain a highly purified Fab2 preparation. The Fc heterologous fragment is responsible for direct complement activation and anaphylactic reactions and its removal makes the product safer for human use. Patients seeking treatment for possible, probable or proven rabies exposure, within a week of exposure with Grade III severity animal bites were explained the trial procedures and written, informed consent was taken before screening for enrollment in the trial. Patients with signs of rabies or history of previous rabies vaccination and those presenting with acute febrile illness (axial temperature >38.5°C) or suffering from chronic immunosuppressive diseases and receiving major immunosuppressive treatment within one month prior to bite were excluded. Patients with positive sensitivity test to ERIG were excluded unless the treating physician considered that the advantages of therapy outweighed the risk involved.

Baseline data recorded were the age and weight of the patient, wound details, the details of the animal responsible for the bite and the rabid status as proven, suspected or unknown. Animals with rabies usually show strange behavior - they can be aggressive, attacking for no apparent reason, or act very tame (especially wild animals), may not be able to eat, drink, or swallow, may drool because they cannot swallow their saliva, and stagger or become paralyzed. The animal may even appear to be healthy. Eventually, the infected animal will die, usually within 10 days. Laboratory tests of the animal’s brain would give a definite diagnosis of rabies4.

Safety evaluation was done on days 3, 7, 14, and 30 after administration of ERIG. Adverse events were classified as immediate (occurring within 24 hours), viz., anaphylactoid reactions with hypotension, dyspnea, urticaria, and delayed (occurring from 24 hours upto 15 days), viz., infl ammatory reaction, fever, pruritus, rash or urticaria, adenopathy and arthralgia. The efficacy evaluation included the absence of any symptoms and signs of rabies during the 30 days’ follow-up.

Wound cleaning with antiseptic solution, soap or water was carried out prior to administration of ERIG. All patients were subjected to intradermal sensitivity test by injecting 0.1 ml in 0.9 ml of saline (1 in 10 dilution) and results observed for 15 minutes. The test was considered positive if the induration was > 10 mm and / or regional edema was seen.

Equirab available in the strength of 1500 iu/5 ml vial was administered in a single dose of 40 IU/kg body weight, of which maximum possible amount was infiltrated locally around and into the wound and remaining was given intramuscularly. The necessary cold chain was maintained by storing the vials in an icebox. After passive immunization was complete, patients were administered rabies vaccine as per the standard protocol. Statistical analysis was generated using SAS software version 8.2 (SAS Institute Inc. Cary, NC, USA) using frequency procedure and means procedure.

Results

177 patients were screened. Nine patients were excluded (7 considered low risk by investigator, 2 with positive sensitivity tests). Of 168 patients enrolled 160 patients were screened for sensitivity test. The other 8 patients received therapeutic dose of ERIG. Six patients were sensitive to ERIG but therapeutic dose of ERIG was administered with the necessary precautions to 4 considered high risk. None of them developed serious side effects.

Table 1: Patient Characteristics at Baseline

S. No. Characteristic Frequency
1. Age (years)* 27.03 + 17.89
2. Weight (kgs)* 42.66 + 17.95
3. Sex
  -Male 131 (78)
  -Female 37(22)
4. Rabid status of the animal
  -Not known 117 (69.6)
  -Suspected 26 (15.5)
  -Non rabid 8(4.8)
  -Rabid 17 (10.1)
5. Grade III bites 166
  Grade II bites 2
*The figures are expressed as Mean + SD and not the frequency
Figures in parentheses indicate the percentages.

The patient characteristics at baseline are shown in Table 1. Majority of the patients (68, 40.5%) had utilized water and soap for initial cleaning of the wound, followed by 18 (10.7%) patients who had used water with soap and antiseptic. Some patients had attempted combination of ingredients to clean the wound and 17 (10%) patients had done no wound toileting.

The mean dose of ERIG given by local infiltration around the wound was 1087.13 IU (±662.2), and by intramuscular route was 781 (±559) (Table 1). Out of 168 patients, ten (5.95%) patients received the entire dose intramuscularly, 31 (18.45 %) patients by local infiltration and the rest by combination of both; information was unavailable about the route of administration in 4 patients. More than 75 % of the calculated dose was injected by local infiltration in 61 (38.6%) patients and 50% to 74% of the dose was infiltrated locally in 58 patients, making a total of 75% patients who received passive immunization predominantly by local infiltration.

None of the patients developed delayed or late adverse events. Immediate adverse drug reaction to ERIG administration was seen in 53 patients (31.5%) and included pain (51), swelling (9), pruritus (6), induration (2) and itching and erythema (1). All these were local. Within the follow up period of 30 days none of the patients developed signs or symptoms of rabies.

Discussion

Rabies ranks ten amongst infectious diseases worldwide and causes about 50,000 to 60,000 human deaths annually although effective vaccines for post exposure treatment are available2. Human rabies is mainly caused by dog bites and annual incidence of bite in India is 1.7%1. Once onset of clinical rabies occurs in an individual, death is inevitable. Thus, it is imperative that for persons exposed or potentially exposed to rabies virus, prophylaxis must be instituted as soon as possible following the exposure. Post exposure prophylaxis, applied adequately, is highly effective in prevention of human disease but its use in India is low (2.1%)1. Deviations from the recommended vaccination post exposure treatment protocol have been associated with vaccination failure and human mortality5. The compliance to vaccine in India is 40.5%1 Hence strict adherence to the treatment protocol is of utmost importance.

ERIG is approximately 1/10th the cost of human rabies immunoglobulin (HRIG), thus an economical preparation for passive immunization3. The safety profile of ERIG was good in our study. It was noteworthy that even the four patients who had demonstrated a positive sensitivity test did not report any untoward reactions. They received Inj.Chlopheniramine and Inj.Hydrocortisone prior to ERIG administration and were observed for 2 hours after ERIG injection.

One month follow up of patients is not sufficient for confirming the effectiveness of ERIG since the incubation period could be longer. However, none of the recruited patients reported any signs and symptoms of rabies within the study period. The WHO Technical Report Series 931 states that without the use of preventive intervention i.e. post-exposure prophylaxis, the total number of predicted human rabies deaths in Asia and Africa would be 330 304 (90% CI: 141 844 – 563 515). Thus, in addition to local wound management, which is an essential part of post exposure rabies prophylaxis, passive immunization with RIG is highly recommended for Grade III animal bites to provide immediate protection against Rabies.

References

  1. Sudarshan MK. Assessing the burden of rabies in India. WHO sponsored national multi-centric rabies survey 2003. Final report. August 2003. Bangalore, Association for Prevention and Control of Rabies in India (APCRI), 2003.
  2. Who Expert Consultation On Rabies. First Report WHO Technical Report Series 931.
  3. Wilde H, Chutivongse S. Equine rabies immunoglobulin: a product with an underserved poor reputation. Am J Trop Med Hyg. 1990; 42(2): 175-8.
  4. Surveillance And Reporting Guidelines For Rabies Post - Exposure Prophylaxis (PEP) Disease Reporting In Washington, Department Of Health, Washington, USA.
  5. Haviv J, Rishpon S, Gdalevich M, Mimouni D, Gross E, Shpilberg O. Successful post exposure rabies prophylaxis after erroneous starting treatment. Prev Med.1999; 29(1): 28-31.

(1)Department of Pharmacology, T N Medical College and BYL Nair Ch Hospital, Mumbai 400 008
(2)Department of PSM, GMC Mumbai
(3)Department of R & D, Bharat Serums and Vaccines Ltd, Mumbai
Received: 08.09.05

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